Pre-pubertal oocytes harbor altered histone modifications and chromatin configuration

Abstract

Pre-pubertal oocytes are still dormant. They are arrested in a GV state and do not undergo meiotic divisions naturally. A multitude of molecular pathways are changed and triggered upon initiation of puberty. It is not yet clear which epigenetic events occur in oocytes upon pubertal transition, and how significant these epigenetic events may be. We evaluated epigenetic marker levels in mouse pre-pubertal and post-pubertal female oocytes. In addition, we evaluated H3K9me2 levels in human oocytes collected from fertility preservation patients, comparing the levels between pre-pubertal patients and post-pubertal patients. The chromatin structure shows a lower number of chromocenters in mouse post-pubertal oocytes in comparison to pre-pubertal oocytes. All heterochromatin marker levels checked (H3K9me2, H3K27me3, H4K20me1) significantly rise across the pubertal transition. Euchromatin markers vary in their behavior. While H3K4me3 levels rise with the pubertal transition, H3K27Ac levels decrease with the pubertal transition. Treatment with SRT1720 [histone deacetylase (HDAC) activator] or overexpression of heterochromatin factors does not lead to increased heterochromatin in pre-pubertal oocytes. However, treatment of pre-pubertal oocytes with follicle-stimulating hormone (FSH) for 24 h - changes their chromatin structure to a post-pubertal configuration, lowers the number of chromocenters and elevates their histone methylation levels, showing that hormones play a key role in chromatin regulation of pubertal transition. Our work shows that pubertal transition leads to reorganization of oocyte chromatin and elevation of histone methylation levels, thus advancing oocyte developmental phenotype. These results provide the basis for finding conditions for in-vitro maturation of pre-pubertal oocytes, mainly needed to artificially mature oocytes of young cancer survivors for fertility preservation purposes.

Epigenetic aging of mammalian gametes

“…All these genes are important for oocyte function (Yuan et al, 2019). Moreover, our own results show the existence of an extensive chromatin remodeling event that occurs in mouse and human oocytes (mouse‐ at 19 days, human‐ before onset of menstrual bleeding) upon exposure to FSH during the pubertal transition (Wasserzug‐Pash et al, 2023). This event also manifests in changes of histone modification patterns, but the specific details are still in need of further investigation.…”

“…The epigenome may also change in resting oocytes during the pubertal transition. Hormonal exposure of the oocytes and surrounding niche cells, as well as structural changes that the ovary itself undergoes during puberty may trigger nuclear and epigenetic changes in mouse and human oocytes (Karavani et al, 2021; Kusuhara et al, 2021; Wasserzug Pash et al, 2023). Previous work has shown that DNA methylation changes during puberty in pig ovaries (at 160 days of age), in promoters of genes that are related to PI3K‐Akt signaling pathway, GnRH signaling pathway, and insulin secretion.…”

Oocyte Aging: A Multifactorial Phenomenon in A Unique Cell

“…Consistent with this, it has been demonstrated that inhibition of reverse-transcriptase activity or artificially increasing heterochromatin levels in aging oocytes abrogates DNA damage and improves oocyte in-vitro maturation efficiency when applied to aged oocytes [ 19 ]. In addition, post-translational histone modifications (PTMs) modulate transcriptional activity [ 21 ] in the egg and, as part of their meiotic function, they are of importance for the processes of kinetochore formation and chromosome segregation [ 22 ]. Noteworthy, changes in histone PTM patterns and DNA methylation are typical for oocyte oogenesis and maturation [ 23 ], and appear to be sensitive in response to stress, stimulation, and aging [ 22 ].…”

“…In addition, post-translational histone modifications (PTMs) modulate transcriptional activity [ 21 ] in the egg and, as part of their meiotic function, they are of importance for the processes of kinetochore formation and chromosome segregation [ 22 ]. Noteworthy, changes in histone PTM patterns and DNA methylation are typical for oocyte oogenesis and maturation [ 23 ], and appear to be sensitive in response to stress, stimulation, and aging [ 22 ]. A recent study provided evidence that the chromatin structure in post-pubertal murine oocytes has fewer chromocenters than prepubertal counterparts, and heterochromatin marker values, such as H3K9me2, H3K27me3, or H4K20me1 increase significantly at the onset of puberty [ 22 ].…”

“…Noteworthy, changes in histone PTM patterns and DNA methylation are typical for oocyte oogenesis and maturation [ 23 ], and appear to be sensitive in response to stress, stimulation, and aging [ 22 ]. A recent study provided evidence that the chromatin structure in post-pubertal murine oocytes has fewer chromocenters than prepubertal counterparts, and heterochromatin marker values, such as H3K9me2, H3K27me3, or H4K20me1 increase significantly at the onset of puberty [ 22 ]. In contrast to the latter-mentioned phenomenon, euchromatic markers behave in a different fashion, namely, H3K4me3 levels are elevated during puberty, whereas H3K27Ac shows lower values [ 22 ].…”